Reciprocal Control of Thyroid Binding and the Pipecolate Pathway in the Brain

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• 作者：André Hallen ; Arthur J. L. Cooper
• 关键词：Ketimine reductase ; l ; Lysine ; ∆¹ ; Piperideine ; 2 ; carboxylate ; Pipecolate pathway ; Saccharopine pathway ; Thyroid binding protein
• 刊名：Neurochemical Research
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：42
• 期：1
• 页码：217-243
• 全文大小：
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Neurosciences; Neurochemistry; Biochemistry, general; Cell Biology; Neurology;
• 出版者：Springer US
• ISSN：1573-6903
• 卷排序：42

文摘

Thyroid hormones have long been known to play an essential role in brain growth and development, with cytoplasmic thyroid hormone binding proteins (THBPs) playing a critical role in thyroid hormone bioavailability. A major mammalian THBP is μ-crystallin (CRYM), which was originally characterized by its ability to strongly bind thyroid hormones in an NADPH-dependent fashion. However, in 2011 it was discovered that CRYM is also an enzyme, namely ketimine reductase (KR), which catalyzes the NAD(P)H-dependent reduction of –C=N– (imine) double bonds of a number of cyclic ketimine substrates including sulfur-containing cyclic ketimines. The enzyme activity was also shown to be potently inhibited by thyroid hormones, thus suggesting a novel reciprocal relationship between enzyme catalysis and thyroid hormone bioavailability. KR is involved in a number of amino acid metabolic pathways. However, the best documented biological function of KR is its role as a ∆^{1-piperideine-2-carboxylate (P2C) reductase in the pipecolate pathway of lysine metabolism. The pipecolate pathway is the main l-lysine degradation pathway in the adult brain, whereas the saccharopine pathway predominates in extracerebral tissues and in infant brain, suggesting that KR has evolved to perform specific and important roles in neural development and function. The potent regulation of KR activity by thyroid hormones adds further weight to this suggestion. KR is also involved in l-ornithine/l-glutamate/l-proline metabolism as well as sulfur-containing amino acid metabolism. This review describes the pipecolate pathway and recent discoveries related to mammalian KR function, which have important implications in normal and pathological brain functions.}